Scientists identify new microbes linked to severe diarrhea

In a finding that may one day help control a major cause of death among children in developing countries, a team of researchers led by faculty from the University of Maryland, College Park and the University of Maryland School of Medicine has identified microorganisms that may trigger diarrheal disease and others that may protect against it. These microbes were not widely linked to the condition previously.

 

"We were able to identify interactions between microbiota that were not previously observed, and we think that some of those interactions may actually help prevent the onset of severe diarrhea," says O. Colin Stine, a professor of epidemiology and public health at the University of Maryland School of Medicine.

A much better understanding of these interactions is important, Stine adds, as they could lead to possible dietary interventions. Moderate to severe diarrhea (MSD) is a major cause of childhood mortality in developing countries and ranks as one of the top four causes of death among young children in sub-Saharan Africa and South Asia.

Stine and Mihai Pop, an associate professor of computer science at the University of Maryland, College Park led the six-year project funded by $10.1 million from the Bill & Melinda Gates Foundation. The research results are available in a paper published in the journal Genome Biology.

The researchers used a technique called high-throughput 16S rRNA genomic sequencing to examine both "good" and "bad" microbiota -- the tens of trillions of microbes that inhabit the human intestinal system -- in samples taken from 992 children in Bangladesh, The Gambia, Kenya and Mali under the age of 5 who were suffering from MSD.

The researchers identified statistically significant disease associations with several organisms already implicated in diarrheal disease, such as members of the Escherichia/Shigella genus and Campylobacter jejuni. They also found that organisms not widely believed to cause the disease, including Streptococcus and Granulicatella, correlated with the condition in their study. In addition, the study revealed that the Prevotella genus and Lactobacillus ruminis may play a protective role against diarrhea.

The project is an offshoot of a $20 million study commissioned by the Gates Foundation in 2006. The Global Enterics Multicenter Study (GEMS) was launched in response to unanswered questions surrounding the burden and etiology of childhood diarrhea in developing countries.

GEMS collected troves of useful data on MSD, yet there were still some uncertainties, says Pop, who also has an appointment in the University of Maryland Institute for Advanced Computer Studies.

For example, in almost 50 percent of the children examined with diarrhea, the condition could not be attributed to a specific causal pathogen. The GEMS research also found numerous children carrying Shigella, which is known to cause problems, yet the children showed no signs of MSD.

The Gates Foundation contacted the two University of Maryland scientists in 2007, looking for new analyses of the GEMS data via a combination of computational biology, epidemiology and public health.

"New technologies have opened up new windows of discovery, so they asked us to look at the samples," says Pop, who adds that he and Stine expect to conduct further genomic and epidemiological studies to assess the potential development of diet- or microbiological-based therapeutics.

Journal Reference:

1. Mihai Pop, Alan W Walker, Joseph Paulson, Brianna Lindsay, Martin Antonio, M Hossain, Joseph Oundo, Boubou Tamboura, Volker Mai, Irina Astrovskaya, Hector Bravo, Richard Rance, Mark Stares, Myron M Levine, Sandra Panchalingam, Karen Kotloff, Usman N Ikumapayi, Chinelo Ebruke, Mitchell Adeyemi, Dilruba Ahmed, Firoz Ahmed, Meer Alam, Ruhul Amin, Sabbir Siddiqui, John B Ochieng, Emmanuel Ouma, Jane Juma, Euince Mailu, Richard Omore, J Morris, Robert F Breiman, Debasish Saha, Julian Parkhill, James P Nataro, O Stine. Diarrhea in young children from low-income countries leads to large-scale alterations in intestinal microbiota composition. Genome Biology, 2014; 15 (6): R76 DOI: 10.1186/gb-2014-15-6-r76 

Courtesy: ScienceDaily

In hairless man, arthritis drug spurs hair growth -- lots

A man with almost no hair on his body has grown a full head of it after a novel treatment by doctors at Yale University.

These panels show the patient's head a) before treatmen with tofacitinib, b) two months into treatment, c) five months into treatment, and d) eight months into treatment.
Credit: Image courtesy of Yale University

There is currently no cure or long-term treatment for alopecia universalis, the disease that left the 25-year-old patient bare of hair. This is the first reported case of a successful targeted treatment for the rare, highly visible disease.
The patient has also grown eyebrows and eyelashes, as well as facial, armpit, and other hair, which he lacked at the time he sought help.
"The results are exactly what we hoped for," said Brett A. King, M.D., assistant professor of dermatology at Yale University School of Medicine and senior author of a paper reporting the results online June 18 in the Journal of Investigative Dermatology. "This is a huge step forward in the treatment of patients with this condition. While it's one case, we anticipated the successful treatment of this man based on our current understanding of the disease and the drug. We believe the same results will be duplicated in other patients, and we plan to try."
The patient had previously been diagnosed with both alopecia universalis, a disease that results in loss of all body hair, and plaque psoriasis, a condition characterized by scaly red areas of skin. The only hair on his body was within the psoriasis plaques on his head. He was referred to Yale Dermatology for treatment of the psoriasis. The alopecia universalis had never been treated.

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King believed it might be possible to address both diseases simultaneously using an existing FDA-approved drug for rheumatoid arthritis called tofacitinib citrate. The drug had been used successfully for treating psoriasis in humans. It had also reversed alopecia areata, a less extreme form of alopecia, in mice.
"There are no good options for long-term treatment of alopecia universalis," said King, a clinician interested in the treatment of rare but devastating skin diseases. "The best available science suggested this might work, and it has."
After two months on tofacitinib at 10 mg daily, the patient's psoriasis showed some improvement, and the man had grown scalp and facial hair -- the first hair he'd grown there in seven years. After three more months of therapy at 15 mg daily, the patient had completely regrown scalp hair and also had clearly visible eyebrows, eyelashes, and facial hair, as well as armpit and other hair, the doctors said.
"By eight months there was full regrowth of hair," said co-author Brittany G. Craiglow, M.D. "The patient has reported feeling no side effects, and we've seen no lab test abnormalities, either."
Tofacitinib appears to spur hair regrowth in a patient with alopecia universalis by turning off the immune system attack on hair follicles that is prompted by the disease, King said.
The drug helps in some, but not all, cases of psoriasis, and was mildly effective in this patient's case, the authors said.
King has submitted a proposal for a clinical trial involving a cream form of tofacitinib as a treatment for alopecia areata.
He cited work by Columbia University scientist Angela Christiano as the reason he decided to try tofacitinib as a therapy in this patient with both alopecia universalis and psoriasis. She has shown that tofacitinib and a related medicine reverse alopecia areata in mice. King called her work exemplary and a clear example of how society's investment in science research leads to improvement in human life.
"This case highlights the interplay between advances in science and the treatment of disease," he said, "and it provides a compelling example of the ways in which an increasingly complex understanding of medicine, combined with ingenuity in treatment, benefits patients."
 

Journal Reference:

1. Brittany G Craiglow, Brett A King. Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in a Patient with Plaque Psoriasis. Journal of Investigative Dermatology, 2014; DOI: 10.1038/jid.2014.260                                                                                                                                             

 Courtesy: ScienceDaily

The ICEMAN study: How keeping cool could spur metabolic benefits

A new study being presented today at ICE/ENDO 2014, the joint meeting of the International Society of Endocrinology and the Endocrine Society in Chicago, demonstrates that ambient temperatures can influence the growth or loss of brown fat in people. Cool environments stimulate growth, warm environments loss.

Brown fat, also known as brown adipose tissue, is a special kind of fat that burns energy to generate heat. It keeps small animals and babies warm, and animals with abundant brown fat are protected from diabetes and obesity. How brown fat is regulated in people, and how it relates to metabolism, have been unclear.
Endocrinologist Dr Paul Lee from Sydney's Garvan Institute of Medical Research, recently undertook The Impact of Chronic Cold Exposure in Humans (ICEMAN) study at the National Institutes of Health (NIH) in Washington, funded as an NHMRC Early Career Research Fellow.
The study results, which clearly show the 'plasticity' of brown fat in humans, are published online today in the journal Diabetes to coincide with the ICE/ENDO meeting.
Lee's previous studies have shown that people with plentiful brown fat stores tend to be lean and have low blood sugar levels. His studies have also shown -- in the laboratory -- that ordinary human white fat cells can change into brown fat cells.

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For the ICEMAN study, 5 healthy men were recruited and exposed to four month-long periods of defined temperature -- well within the range found in climate-controlled buildings -- at the NIH Clinical Centre. They lived their normal lives during the day, and returned each night to the centre, staying for at least 10 hours in a temperature-regulated room.
For the first month, the NIH rooms were maintained at 24º C, a 'thermo-neutral' temperature at which the body does not have to work to produce or lose heat.
The temperature was then moved down to 19º C for the second month, back to 24º for the third month, and up to 27º for the fourth month.
At the end of each month, participants underwent a detailed 'thermal metabolic evaluation' in a whole room calorimeter. Measurements taken at the end of the first month represented 'baseline'.
In addition, cold-stimulated PET/CT scans measured brown fat, and muscle and fat biopsies revealed tissue metabolic changes.
Independent of the season during which the study was carried out, brown fat increased during the cool month and fell during the warm month.
Among the metabolic benefits of increased brown fat was heightened insulin sensitivity. This suggests that people with more brown fat require less insulin after a meal to bring their blood sugar levels down.
"The big unknown until this study was whether or not we could actually manipulate brown fat to grow and shrink in a human being," said Dr Lee.
"What we found was that the cold month increased brown fat by around 30-40%."
"During the second thermo-neutral month at 24 degrees, the brown fat dropped back, returning to baseline."
"When we put the temperature up to 27 degrees during the fourth month, the volume of brown fat fell to below that of baseline."
Dr Lee sees promise in brown fat for people with diabetes, whose bodies have to work hard to bring sugar levels down after a meal.
"The improvement in insulin sensitivity accompanying brown fat gain may open new avenues in the treatment of impaired glucose metabolism in the future. On the other hand, the reduction in mild cold exposure from widespread central heating in contemporary society may impair brown fat function and may be a hidden contributor to obesity and metabolic disorders," Lee said.
"Studies have been performed in the UK and US measuring bedroom, dining room and lounge room temperatures in people's homes over the last few decades, and the temperature has climbed from about 19 to 22, a range sufficient to quieten down brown fat."
"So in addition to unhealthy diet and physical inactivity, it is tempting to speculate that the subtle shift in temperature exposure could be a contributing factor to the rise in obesity."
Journal Reference:

1. Paul Lee, Sheila Smith, Joyce Linderman, Amber B Courville, Robert J Brychta, William Dieckmann, Charlotte D Werner, Kong Y Chen, and Francesco S Celi. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes, June 22, 2014 DOI: 10.2337/db14-0513 

Courtesy: ScienceDaily

Strict diet suspends development, doubles lifespan of worms

The centuries-long search for the fountain of youth has yielded only a few promising leads, one of which entails an extreme, emaciating diet. A new study of the tiny nematode worm C. elegans begins to explain this marvel of calorie restriction and hints at an easier way to achieve longevity.

Researchers at Duke University found that taking food away from C. elegans triggers a state of arrested development: while the organism continues to wriggle about, foraging for food, its cells and organs are suspended in an ageless, quiescent state. When food becomes plentiful again, the worm develops as planned, but can live twice as long as normal.
The results appear June 19 in PLOS Genetics.
"It is possible that low-nutrient diets set off the same pathways in us to put our cells in a quiescent state," said David R. Sherwood, an associate professor of biology at Duke University. "The trick is to find a way to pharmacologically manipulate this process so that we can get the anti-aging benefits without the pain of diet restriction."
Over the last 80 years, researchers have put a menagerie of model organisms on a diet, and they've seen that nutrient deprivation can extend the lifespan of rats, mice, yeast, flies, spiders, fish, monkeys and worms anywhere from 30 percent to 200 percent longer than their free-fed counterparts.

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Outside the laboratory and in the real world, organisms like C. elegans can experience bouts of feast or famine that no doubt affect their development and longevity. Sherwood's colleague Ryan Baugh, an assistant professor of medicine at Duke, showed that hatching C. elegans eggs in a nutrient-free environment shut down their development completely. He asked Sherwood to investigate whether restricting diet to the point of starvation later in life would have the same effect.
Sherwood and his postdoctoral fellow Adam Schindler decided to focus on the last two stages of C. elegans larval development -- known as L3 and L4 -- when critical tissues and organs like the vulva are still developing. During these stages, the worm vulva develops from a speck of three cells to a slightly larger ball of 22 cells. The researchers found that when they took away food at various times throughout L3 and L4, development paused when the vulva was either at the three-cell stage or the 22-cell stage, but not in between.
When they investigated further, the researchers found that not just the vulva, but all the tissues and cells in the organism seemed to get stuck at two main checkpoints. These checkpoints are like toll booths along the developmental interstate. If the organism has enough nutrients, its development can pass through to the next toll booth. If it doesn't have enough, it stays at the toll booth until it has built up the nutrients necessary to get it the rest of the way.
"Development isn't a continuous nonstop process," said Schindler, who is lead author of the study. "Organisms have to monitor their environment and decide whether or not it is amenable to their development. If it isn't, they stop, if it is, they go. Those checkpoints seem to exist to allow the animal to make that decision. And the decision has implications, because the resources either go to development or to survival."
The study found that C. elegans could be starved for at least two weeks and still develop normally once feeding resumed. Because the meter isn't running while the worm is in its arrested state, this starvation essentially doubles the two-week lifespan of the worm.
"This study has implications not only for aging, but also for cancer," said Sherwood. "One of the biggest mysteries in cancer is how cancer cells metastasize early and then lie dormant for years before reawakening. My guess is that the pathways in worms that are arresting these cells and waking them up again are going to be the same pathways that are in human cancer metastases."
The researchers are now performing a number of genetic studies to see if they can find another way to force C. elegans into these development holding patterns.

Journal Reference:

1. Adam J. Schindler, L. Ryan Baugh, David R. Sherwood. Identification of Late Larval Stage Developmental Checkpoints in Caenorhabditis elegans Regulated by Insulin/IGF and Steroid Hormone Signaling Pathways. PLoS Genetics, 2014; 10 (6): e1004426 DOI: 10.1371/journal.pgen.1004426

Courtesy: ScienceDaily